Perivascular delivery of neomycin inhibits the activation of NF-κB and MAPK pathways, and prevents neointimal hyperplasia and stenosis after arterial injury

Abstract

The nuclear transcription factor kappaB (NF-κB) is a cytoplasmic dimer that, as the family of mitogen-activated protein kinase (MAPK), can directly regulate the expression of early genes and genes involved in the stress response, following a variety of physiological or pathological stimuli. Both of them stimulate the transcription of many proteins, which are considered important during inflammation. A crucial role has been assigned to these factors in cellular proliferation and in neointimal hyperplasia secondary to the endothelial lesion of arterial vessels. On the other hand, it has been described that neomycin can have an inhibitory function on tumor cell proliferation, through the inhibition of different intracellular pathways of signaling, among them the NF-κB and MAPK pathways. Rat common carotid artery was subjected to balloon angioplasty. Neomycin sulfate (18 mg) was applied using pluronic acid gel on the adventitial surface of the injured vessel. MAPK and NF-κB activation was quantified after 24 hours with immunohistochemical staining. Neointimal formation was quantified after 14 days with morphometry. Immunohistochemistry results demonstrating MAPK and NF-κB activation reveal that both transcription factors are activated in the media of the control vessel wall. In contrast, the immunoreactivity for MAPK and NF-κB in the sections obtained from arteries treated with neomycin over 24 hours was insufficient or nonexistent. Treatment with neomycin on adventitia over 14 days in arteries on which angioplasty was performed shows a neointimal index (intimal area/medial area) decrease of 71% in comparison with arteries that were not treated. The adventitial neomycin treatment over 14 days produces a very significant increase (287.5%; p<0.0001) in the arterial luminal circumference in comparison with arteries treated with vehicle. These results support the theory that neomycin plays an important role against neointimal hyperplasia through the inhibition of MAPK and NF-κB activation.